Biodegradable polyamides

ABSTRACT

Biodegradable polyamides, useful as absorable sutures and as controlled release binder materials, are prepared by condensing 4,4&#39;-spirobibutyrolactone with a primary diamine, optionally in the presence of a nylon salt, leading to homopolymers containing lactam structural units, or to random copolymers.

This invention is in the field of organic polymer chemistry. Morespecifically, this invention relates to novel polyamides having bothpendant hydroxyl functionality and lactam groups in the polymerbackbone. These polymers are compatible with living tissue and arebiodegradable, making them especially useful as absorbable suturematerials and controlled release carrier, encapsulating, or excipientmaterials for bio-active agents, for example.

In one aspect, homopolymers of this invention are prepared by openingthe lactone rings of difunctional 4,4'-spirobibutyrolactone (SBBL) witha diamine. In another aspect of this invention, a copolymer is producedwhen the aforesaid polymerization is carried out in the presence of adibasic acid and additional diamine.

Homopolymers similar to those of this invention were disclosed in U.S.Pat. No. 4,064,086, which describes both a linear polyamide containinghydroxyl groups, and adducts thereof crosslinked with diisocyanates viathe pendant hydroxyl groups. The homopolymers of the instant inventionare distinguished from the polyamides of U.S. Pat. No. 4,064,086 interms of the method by which they are prepared and their chemicalstructure. The homopolymers of the instant invention include lactamgroups. Although the polymers disclosed in U.S. Pat. No. 4,064,086 werecharacterized as thermoplastic hydrogels, biodegradation was notdisclosed.

Sutures may be classified as absorbable or nonabsorbable, and absorbablesutures may be monofilaments or multifilaments. The absorbable suturesare typically either synthetic materials, such as poly(glycolide),poly(lactide-co-glycolide), or natural materials such as silk andcatgut. Due to their high modulus of elasticity, the synthetic suturesare stiffer than natural catgut or silk; therefore they are employed asbraided multifilament yarns to reduce the stiffness. Braiding isdetrimental because the added surface roughness may actually abradethrough weak tissues. Braided sutures may also inhibit knot run-down dueto surface roughness of the braid, and coatings are routinely applied toserve as lubricants.

There are wide variations in tissue types, degrees of trauma, and ratesof healing. Although several attempts have been made, no one hasdeveloped an ideal suture material; consequently, a need exists forsuture materials in a variety of strengths, sizes, and rates ofdegradation. There are, however, several desirable characteristics thatall absorbable sutures should possess. The material should have goodhandling characteristics. It should hold tissue for proper healing withminimal tearing and tissue damage; it should have good tensile and knotstrength; it should be capable of being easily tied into stable surgicalknots; it should be dimensionally stable in the body; it should besterilizable; and it should be absorbable by living tissue withoutcausing adverse reactions. While numerous materials have been andcontinue to be investigated for use as absorbable sutures, none hascompletely satisfied all these criteria.

It is known that nylons 6- and 6,6 eventually degrade in vivo, but theirrates of biodegradation are too slow for most practical uses. Certainpolyamides, such as alpha-benzoylated nylon 6,3 and the alternatingcopolymers of glycine (nylon 2)/nylon 6 and serine/nylon 6, areconsiderably more susceptible to biodegradation than either nylon 6 ornylon 6,6.

Materials that have been proposed to resolve the stiffness probleminclude the copolyoxalates, copolymers of p-dioxanone and otherpoly(ether esters), and poly(ester amides). In the poly(ether ester)series, flexibility is imparted by the presence of the ether linkages;the same linkages increase the hydrophilicity of the polymer, enhancingthe overall rate of hydrolysis or biodegradation. Chain flexibility instraight-chain aliphatic polyesters can be increased by increasing thelength of the aliphatic chain. However, increasing the aliphatic chainlength causes a simultaneous decrease in hydrophilicity and in the rateof hydrolysis.

Thus, an objective of the instant invention is to produce a series ofpolyamides which overcomes the several problems of the prior artabsorbable suture materials. This objective is attained in novel organicpolymers, the structural formula of which includes a backbone containingn biradical units of the formula ##STR1## joined randomly with mbiradical units of the formula ##STR2## wherein

n is a positive integer;

m is either zero or a positive integer; each R independently is ahydrocarbon radical;

X₁ is --OH and Y₁ is --H, or X₁ and Y₁ together constitute a chemicalbond in a lactam ring;

X₂ is --OH and Y₂ is --H, or X₂ and Y₂ together constitute a chemicalbond in a lactam ring;

said backbone being capped with a radical selected from ##STR3## --NH₂,and also ##STR4## when m is a positive integer;

with the proviso that the polymer contains lactam units when m is zero.

It will be recognized that polymers within the aforesaid description mayexist as isomers, including stereoisomers, and it should be understoodthis invention contemplates and includes all such isomers.

In the event that m is zero, the aforesaid description includes a seriesof homopolymers which are prepared by condensing4,4'-spirobibutyrolactone with various primary diamines. The resultinghomopolymers of this invention include lactam units within theirstructural formulae. These lactam units may be viewed formally asproduced by elimination of water between X₁ and Y₁, or X₂ and Y₂. Amongthe possible homopolymers obtainable by varying the nature of thediamine, it is preferred that the hydrocarbon radical R be aliphatic oralicyclic and that it contain 4-14 carbon atoms. Among the aliphaticdiamines, pentamethylenediamine and hexamethylenediamine are especiallyuseful, and hexamethylenediamine is preferred. Examples of usefulalicyclic diamines are 1,4-cyclohexanebis(methylamine) and4,4'-methylenebis(cyclohexylamine). Other useful diamines are disclosedin U.S. Pat. No. 4,064,086, incorporated herein by reference.

When both n and m are positive integers, the aforesaid descriptionincludes copolymers of 4,4'-spirobibutyrolactone and a first diaminecombined with a nylon derived from a dibasic acid and a second diamine.Although the first and second diamines need not be the same, it ispreferred that they are the same in order to simplify the polymerstructure and minimize the number of reactants. Preferred diaminesinclude aliphatic and alicyclic diamines having 4-14 carbon atoms,especially those named above in connection with the homopolymers.Pentamethylenediamine and hexamethylenediamine are especially useful.Although wide variations are possible in the dibasic acid, it ispreferred that the dibasic acid component of the nylon be aliphatic andcontain 3-9 carbon atoms. Glutaric and especially adipic acid arepreferred. Although the copolymers of this invention may contain lactamunits in their structural formulae, that feature is not a requisiteelement.

The properties of a copolymer containing a given nylon are dependentupon the lactone/nylon ratio. This ratio may vary from about 90/10 toabout 10/90, but the ratio is preferably in the range 25/75 to 75/25. A50/50 ratio provides a polymer especially useful for sutures when one ofthe polymer units is nylon 6,6 and hexamethylenediamine is also presentin the lactone portion.

In the description which follows, the polymers of this invention aresometimes referred to using a condensed nomenclature scheme similar tothat employed for nylons, in which the term "6,6", for example, refersto the polymer of hexamethylenediamine (the first "6") and adipic acid(the second "6"). Accordingly, "6,S5" refers to the homopolymer ofhexamethylenediamine, sometimes also referred to as "HMDA", and4,4'-spirobibutyrolactone, while "6,S5:6,6 (50:50)" refers to the 50:50(mol:mol) copolymer of hexamethylenediamine,4,4'-spirobibutyrolactone:hexamethylenediamine, adipic acid.

The polymers within the scope of this invention are prepared by varioustechniques. The homopolymers can be prepared by reacting4,4'-spirobibutyrolactone (SBBL) directly with the desired diamine.Alternatively, it may be advantageous to prepare the polymer from apreformed salt of 3,3-bis(hydroxymethyl)glutaric acid (BHMGA) and thediamine. Copolymers within the scope of this invention are convenientlyprepared by reacting a nylon salt containing the desired dibasic acidand diamine with either the lactone/diamine mixture or the appropriateglutarate/diamine salt. These syntheses are illustrated below.

The inherent viscosities (IV's) of SBBL-containing polyamides weredetermined in trifluoroethanol at a concentration of 0.5 g/dL at 30° C.Infrared spectra were obtained from thin films on NaCl plates.

An estimate of the lactone and lactam groups in the homopolymers wasobtained from IR spectra by comparing the ratios of the lactone carbonylstretch to the amide II absorptions and the amide I to amide IIabsorptions, respectively. These ratios were calculated from the peakareas of the respective absorptions in the IR spectra. A polymerconsisting of acyclic secondary amide groups alone should show nocontribution by lactone carbonyl (abt. 1775 cm⁻¹), and the lactonecarbonyl/amide II ratio should be zero. Similarly, this polymer shouldhave an amide I/amide II ratio of about 1.1, which is the case for nylon6,6. Because the lactam structure gives rise to an amide I band, but noamide II band, amide I/amide II ratios greater than about 1.1 should beindicative of polymers containing lactam groups. Therefore, the largerthe amide I/amide II ratio, the greater the amount of lactam present inthe polymer. Similarly, the larger the lactone carbonyl/amide II ratio,the greater the amount of lactone present.

Model compounds can be employed to quantify the lactone, lactam andsecondary amide structures present in the polymer. Three model compounds(gamma-butyrolactone, N-methylpyrrolidone, and N-methylacetamide) werechosen as materials representative of carbonyl groups present in thepolymers. Furthermore, these compounds were all liquids at roomtemperature, which permitted IR spectra under the same conditions as thepolymers (i.e., in an amorphous phase). Binary solutions ofgamma-butyrolactone/N-methylacetamide andN-methylpyrrolidone/N-methylacetamide of known mol % were prepared, andan IR spectrum (linear absorbance mode) of each solution was obtained.From each IR spectrum, the areas under the lactone, amide I, and amideII absorptions were determined. Areas were determined by weighing threephotocopy cutouts of each absorption and determining an average weight.Two calibration curves were then plotted: log(amide I/amide II) vs mol %N-methylpyrrolidone and lactone carbonyl/amide II vs mol %gamma-butyrolactone. From these two plots, the percentage of eachcarbonyl species in a homopolymer could be calculated. The resultsobtained using the IR analysis described above were compared in a fewcases with results obtained by more costly and time-consuming NMRanalyses; based on that comparison, the conclusions reached using IRanalysis and reported below should be viewed as semiquantitative.

The polymer molecular weights set forth in the Tables which follow weredetermined by IR end group analysis, assuming one lactone end group perpolymer chain, unless it is indicated the molecular weights weredetermined by vapor phase osmometry (VPO).

EXAMPLE I Salt of 3,3-Bis(Hydroxymethyl)glutaric Acid andHexamethylenediamine

SBBL was synthesized in four steps from dibromopentaerythritol in amanner similar to that described in U.S. Pat. No. 4,064,086.

SBBL (20.0 g, 0.128 mol) was treated with two equivalents of aqueousNaOH (1.0 M) at room temperature, and in a separate flask,hexamethylenediamine (HMDA, 14.87 g, 0.128 mol) was combined with anequivalent amount of 2.0 N H₂ SO₄. The solutions were combined, and themajority of the water was removed with a rotary evaporator. Anhydrousethanol (500 ml) was added to the flask, and the precipitate (Na₂ SO₄)was removed by filtration. The filtrate was reduced in volume to an oil,and fresh ethanol was added. The remainder of the water was removed viaazeotropic distillation with ethanol until a white solid formed in theflask. The solid was washed thoroughly with ethanol, filtered and driedin vacuo overnight at room temperature, affording 35.2 g (89%) of thepolysalt of 3,3-bis(hydroxymethyl)glutaric acid (BHMGA) and HMDA, mp132°-133° C. (dec).

EXAMPLE II Homopolymer of SBBL and HMDA (6,S5)

A. From SBBL/HMDA

To a glass-lined pressure vessel was added 25.35 g (0.162 mol) of SBBLand 20.0 g (0.172 mol) of HMDA. The vessel was sealed, deoxygenated bypressurization-depressurization with N₂, and finally pressurized to 100psig with N₂. The vessel was immersed in an oil bath at 240° C. for 3hrs and then allowed to cool to room temperature. The glass linercontaining the product was placed inside a glass tube of largerdiameter, and a vacuum (abt. 1 mm Hg) was applied to the apparatus. Theassemblage was heated gradually to 230° C. under vacuum, and it wasmaintained at that temperature for 3 hrs. The molten mass was thencooled slowly to 120° C., where it was maintained for 1.5 hr. and thenallowed to cool slowly to room temperature. The resultant straw-coloredproduct had an IV of 1.00 dL/g.

B. From BHMGA/HMDA Salt.

In a glass liner was placed 5.99 g (0.0194 mol) of3,3-bis(hydroxymethyl)glutaric acid/HMDA salt and 0.14 g (0.0012 mol) ofHMDA. The liner was sealed inside a stainless steel pressure vessel anddeoxygenated and pressurized with N₂ (100 psig) as described in ExampleIIA. The vessel was placed in an oil bath and maintained at 240° C. for4 hr and then was allowed to cool to room temperature. The resultantprepolymer was dried overnight at room temperature under vacuum. Theprepolymer was then heated under vacuum (about 1 mm Hg) to 230° C.,maintained at that temperature for 3 hr, and then slowly cooled to 130°C. over 2 hr, and then held at 130° C. for 1.5 hr. The polymer was thenallowed to cool to room temperature under vacuum. The IV of the productwas 1.05 dL/g.

Tables 1-3 illustrate the effect of various reaction conditions on theproduct obtained from the BHMGA/HMDA salt.

                                      TABLE 1                                     __________________________________________________________________________    HOMOPOLYMERIZATION OF BHMGA/HMDA SALT                                         AT CONSTANT TEMPERATURE (l70° C.) AND                                  PRESSURE (130 psig N.sub.2)                                                         Initial                                                                            Reaction                                                           Sample No.                                                                          pressure                                                                           time,                                                                              IV,                                                                              Lactone,                                                                           Lactam,                                                                            2° Amide,                                 C790  N.sub.2, psig                                                                      h    dL/g                                                                             mol %                                                                              mol %                                                                              mol % -- M.sub.n                                 __________________________________________________________________________    133-1 130.sup.a                                                                          24   0.19                                                                             2    57   41    --                                         137-1.sup.b                                                                         --.sup.c                                                                           --   0 36                                                                             4    52   44    3250                                       134-1 130.sup.a                                                                          12   0.15                                                                             5    43   52    --                                         137-2.sup.b                                                                         --.sup.c                                                                           --   0.25                                                                             5    66   29    2530                                       135-1 130.sup.a                                                                           6   0.12                                                                             3    29   68    --                                         137-3.sup.b                                                                         --.sup.c                                                                           --   0.16                                                                             12   47   41    1100                                       136-1 130.sup.a                                                                           3   0.12                                                                             4     0   96    --                                         137-4.sup.b                                                                         --.sup.c                                                                           --   0.14                                                                             11   65   24    1130                                       __________________________________________________________________________     .sup.a Added 0.2 mL H.sub.2 O/2.0 g salt.                                     .sup.b Vacuum step performed on postpressure polymer of preceding entry.      .sup.c RT to 210°  C., l h (0.1 mm); 210° C., l h (0.1 mm);     210° C., to 100° C., 1 h (0.1 mm).                         

                                      TABLE 2                                     __________________________________________________________________________    HOMOPOLYMERIZATION OF BHMGA/HMDA SALT                                         AT CONSTANT TIME (24 H) AND                                                   TEMPERATURE (160° C.)                                                             Initial                                                                  pressure                                                                           pressure                                                                            Final                                                        Sample No.                                                                          N.sub.2,                                                                           N.sub.2 + H.sub.2 O,                                                                IV,                                                                              Lactone,                                                                           Lactam,                                                                            2° Amide,                                C790  psig psig  dL/g                                                                             mol %                                                                              mol %                                                                              mol % -- M.sub.n                                __________________________________________________________________________    142-1  0.sup.a                                                                            60   0.11                                                                             6     0   94    --                                        142-2.sup.b                                                                         --.sup.c                                                                           --    0.18                                                                             7    63   30    1860                                      143-1  50.sup.a                                                                          135   0.12                                                                             6    19   75    --                                        143-2.sup.b                                                                         --.sup.c                                                                           --    0.20                                                                             5    66   29    2590                                      144-1 100.sup.a                                                                          205   0.12                                                                             7    25   68    --                                        144-2.sup.b                                                                         --.sup.c                                                                           --    0.19                                                                             5    62   33    2310                                      145-1 150.sup.a                                                                          275   0.12                                                                             7    27   66    --                                        145-2.sup.b                                                                         --.sup.c                                                                           --    0.18                                                                             6    63   31    2110                                      146-1 200.sup.a                                                                          360   0.13                                                                             7    25   68    --                                        146-2.sup.b                                                                         --.sup.c                                                                           --    0.19                                                                             6    58   36    2100                                      __________________________________________________________________________     .sup. a Added 5.0 mL H.sub.2 O/2.0 g salt.                                    .sup.b Vacuum step performed on postpressure polymer of preceding entry.      .sup.c RT to 170° C. (200 mm); 170° C., 20 h (200 mm).     

                                      TABLE 3                                     __________________________________________________________________________    HOMOPOLYMERIZATION OF BHMGA/HMDA                                              SALT FOR 24 H                                                                            Initial                                                            Sample No.                                                                          pressure                                                                           Temp,                                                                             IV,                                                                              Lactone,                                                                           Lactam,                                                                            2° Amide,                                  C790  N.sub.2, psig                                                                      °C.                                                                        dL/g                                                                             mol %                                                                              mol %                                                                              mol % -- M.sub.n                                  __________________________________________________________________________    150-l  0.sup.a                                                                           160 0.13                                                                             7    32   61    --                                          150-2.sup.b                                                                         --.sup.c                                                                           --  0.17                                                                             7    52   41    1890                                        151-1 200.sup.a                                                                          160 0.15                                                                             6    36   58    --                                          151-2.sup.b                                                                         --.sup.c                                                                           --  0.18                                                                             6    46   48    2240                                        152-1  0.sup.a                                                                           170 0.15                                                                             5    39   56    --                                          152-2.sup.b                                                                         --.sup.c                                                                           --  0.19                                                                             5    50   45    2350                                        153-1 200.sup.a                                                                          170 0.16                                                                             7    41   52    --                                          153-2.sup.b                                                                         --.sup.c                                                                           --  0.20                                                                             4    59   37    2990                                        __________________________________________________________________________     .sup.a No H.sub.2 O added.                                                    .sup.b Vacuum step performed on postpressure polymer of preceding entry.      .sup.c RT to 200° C., 1 h (760 mm); 200° C., 1 h (240 mm);      200° C. to 100° C., 1 h (240 mm to 5 mm)                   

In general, optimum production of both homopolymers and copolymershaving reasonably high molecular weights utilizes a three-step process.In the first step, the reactants are melted (generally about 230°-250°C.) under inert gas pressure (e.g., 100 psig N₂ initial pressure) forabout 3-4 hours to effect oligomerization. A 1-5 percent excess ofdiamine may be utilized. In the second step, the prepolymer is heated(usually above 200° C.) under vacuum, e.g., 1-10 mm Hg, to melt it; thisis continued until the melt thickens and the evolution of gas slows,typically 2-3 hours. In the third stage, the polymer is allowed to cooland is then held at 100°-140° C. for several (typically 3-4) hours inthe solid state. If the polymer is held at this temperature too long,cross-linking may occur. The cross-linking can be reversed, however, byreheating the polymer above its melting temperature and the third stagerepeated.

The properties of other homopolymers similarly prepared are shown inTable 4.

                  TABLE 4                                                         ______________________________________                                        EXAMPLES OF OTHER HOMOPOLYMERS                                                CONTAINING SBBL                                                                        Polymer type IV,                                                     Sample No.                                                                             and composition.sup.a                                                                      dL/g    -- M.sub.n (VPO)                                                                      Method                                  ______________________________________                                        E179-15-1                                                                              6,S5         1.00    4,300   II A.                                   D526-73-1                                                                              6,S5         1.05            II B.                                   E179-22-1                                                                              C8,S5.sup.c  0.61    4,300   II A.                                   D526-107-2                                                                             5,S5         0.48            II A.                                   D526-116-2                                                                             P,S5.sup.b   0.08            II A.                                   D526-120-2                                                                             C13,S5       0.11            II A.                                   ______________________________________                                         .sup.a Diamine/diacid. Diamines: 5 = 1,5pentanediamine; 6 =                   1,6hexanediamine; P = piperazine; C8 = 1,4cyclohexanebis(methylamine); C1     = 4,4methylenebis-(cyclohexylamine).                                          .sup.b Outside the scope of this invention.                                   .sup.c Other samples of C8,S5 polymers, separately prepared, were             crosslinked with hexamethylenediisocyanate and spun into fibers.         

EXAMPLE III Copolymer of BHMGA/HMDA and Nylon; 6S5:6,6 (50:50)

To a glass liner was added 35.2 g (0.114 mol) of BHMGA/HMDA salt, 29.95g (0.114 mol) of nylon 6,6 salt, and 0.84 g (0.0072 mol) of HMDA. Theliner was placed inside a pressure vessel and then deoxygenated andpressurized with N₂ as described above. The vessel was heated at 240° C.for 4 hrs and cooled. The mass was heated in vacuo to 230° C.,maintained at 230° C. for 3 hrs, cooled slowly to 135° C., andmaintained at 135° C. for 16 h. The resultant copolymer would notdissolve in the usual solvents. The mass was reheated to 225° C. invacuo where it became molten. (1.5 h) and then was recooled to roomtemperature. The copolymer was soluble at this stage and had an IV of0.78 dL/g. The remainder of the sample was heated in a vacuum oven at110° C. for 4 hrs. The IV of the resultant copolymer was 1.75 dL/g.

Substantially the same copolymers can also be prepared by using SBBL andHMDA in place of the BHMGA/HMDA salt. The properties of other copolymerssimilarly prepared, but incorporating SBBL and other diamines or dibasicacids are shown in Table 5.

                  TABLE 5                                                         ______________________________________                                        EXAMPLES OF OTHER COPOLYMERS                                                  CONTAINING SBBL                                                                       Polymer                                                                       type and    IV,                                                       Sample No.                                                                            composition.sup.a                                                                         dL/g      -- M.sub.n (VPO)                                                                      Method                                  ______________________________________                                        C790-124-2                                                                            6,S5:6,6    (25:75) 1.12      SALT                                    D526-82-2                                                                             6,S5:6,6    (50:50) 1.75      SALT                                    D526-83-2                                                                             6,S5:6,6    (50:50) 1.78                                              E179-24-1.sup.b                                                                       6,S5:6,6    (50:50) 1.80                                                                            17,400                                          D526-39-2                                                                             6,S5:6,6    (60:40) 0.77      SALT                                    D526-70-1                                                                             6,S5:6,6    (75:25) 0.98      SALT                                    D526-128-2                                                                            4,S5:4,6    (50:50) 0.53                                              D526-110-2                                                                            5,S5:5,5    (50:50) 0.47                                              D526-111-2                                                                            6,S5:6,5    (50:50) 0.33                                              E179-28-1.sup.b                                                                       C8,S5:C8,6  (50:50) 1.54                                                                             7,200                                          D526-124-2                                                                            C13,S5:C13,6                                                                              (50:50) 0.34                                              ______________________________________                                         .sup.a Diamine, SBBL: nylon diamine, diacid (mol:mol). Diamines: 4 =          1,4butanediamine; 5 = 1,5pentanediamine; 6 = 1,6hexanediamine (HMDA); C8      1,4cyclohexanebis(methylamine); C13 = 4,4methylenebis(cyclohexylamine).       Diacids: 5 = glutaric acid; 6 = adipic acid.                                  .sup.b Reprecipitated sample.                                            

It will be evident that both the homopolymers and the copolymers of thisinvention can be cross-linked with difunctional reagents which reactwith pendant hydroxyl groups, e.g., diisocyanates. Suitable difunctionalreagents as well as the manner of their reaction to cross-link polymersof the general nature described herein are set forth in U.S. Pat. No.4,064,086, incorporated herein by reference.

The utility of polyamides within the scope of this invention wasevaluated in fiber-spinning trials, by in vitro hydrolysis studies, byin vivo implantation experiments, and by measuring the controlledrelease of bio-active agents from drug/polyamide blends. Results ofthese experiments are presented below.

EXAMPLE IV Fiber Spinning

A sample of 6,S5:6,6 (50:50) copolymer (IV 0.78) was employed infiber-spinning trials. Monofilaments were melt spun on a ram extruder(0.6 in. diameter bore) in two spinning trials. The first trial was madewith a spinneret having a single orifice 0.020 in. in diameter and 0.040in. in length to determine the approximate spinneret size and spinningconditions required for preparing monofilament suitable for orienting toa 4-0 suture size. A second trial was then made with a spinneret havinga single 0.047 in. diameter orifice about 0.094 in. in length to preparea sufficient quantity of monofilament with a 4-0 suture size forevaluation. The conditions used in each of these spinning trials aregiven in Table 6.

The monofilaments were oriented on a draw winder. The conditions usedfor orienting each sample are given in Table 7.

The diameters of the oriented fibers were measured on a Zeiss polarizingmicroscope equipped with an eyepiece micrometer disk. The tensileproperties were measured on an Instron tester with a gauge length of 5in. and a crosshead speed of 5 in./min. The chart speed was also 5in./min. The diameters and tensile properties of the fibers are alsogiven in Table 7.

                  TABLE 6                                                         ______________________________________                                        MELT-SPINNING CONDITIONS AND                                                  DIAMETER OF MONOFILAMENTS                                                     Melt-spinning  Sample B285                                                    conditions                                                                    81-1                                                                          81-2                                                                          85-1                                                                          85-2                                                                          ______________________________________                                        Block temp, °C.                                                                       206     206      203   203                                     Feed rate, cm.sup.3 /min                                                                     0.5     0.5      0.5   0.5                                     Ram pressure, psi                                                                            105     150      35    65                                      Take-up speed, ft/min                                                                        25.0    43.0     12.0  11.5                                    Diameter, mils (approx)                                                                      8       6        14    14                                      ______________________________________                                    

                                      TABLE 7                                     __________________________________________________________________________    ORIENTING CONDITIONS, DIAMETER, AND                                           TENSILE PROPERTIES OF MONOFILAMENTS                                           Orienting conditions                                                          diameter, and                                                                           Sample B285     Polypro-                                                                           Nylon                                          tensile properties                                                            81-1-2                                                                        81-2-3                                                                        85-1-2                    pylene.sup.a                                                                       6,6                                            __________________________________________________________________________    Draw ratio                                                                              6.3X 6.1X 6.3X                                                      Plate temp. °C.                                                                  80   80   80                                                        Diameter, mm                                                                            0.0980                                                                             0.0882                                                                             0.1764                                                                              0.2399                                                                             0.1650                                         Suture size                                                                             6-0  6-0  4-0   3-0  4-0                                            Denier    76   68   224   413  283                                            Tenacity, g/d                                                                           1.61 1.46 1.39  5.2  4.7                                            Elongation at                                                                           22   23   27    43.4 36.6                                           break, %                                                                      Initial modulus,                                                                        10.1 19.9 19.5                                                      g/d                                                                           Initial modulus,                                                                        4.53 9.86 7.96  3.43 4.96                                           psi -10.sup.5                                                                 Tensile factor                                                                          7.5  7.0  7.2   34.3 28.4                                           Moisture regain, %                                                                      --   --   --    --   5.4                                            __________________________________________________________________________     .sup.a Commercial suture material outside the scope of this invention.   

EXAMPLE V In Vitro Hydrolysis Studies

Accelerated Studies: 90° C. A weighed amount (abt. 0.2 g) of granulatedpolymer (to pass a #20 mesh sieve) was placed in each of several 10-mLserum vials, and 10-mL of 0.2 M NaH₂ PO₄ (adjusted to pH 7.2) was added.The vials (14 per polymer) were placed in an oven maintained at 90° C.,and vials were removed periodically. The polymer residues in the vialswere recovered by filtration or isolated by drawing off the buffersolution via pipet, and they were dried in vacuo at room temperature forat least 18 hr. The polymer residues were reweighed, and the percentageof mass recovered for each residue was calculated; the results appear inTable 8.

                  TABLE 8                                                         ______________________________________                                        IN VITRO HYDROLYSIS (90° C.)                                           % Mass Recovered                                                              Sample:                                                                       Time/                   6,S5:6,6                                                                              6,S5:6,6                                                                             6,S5:6,6                               day   PCL.sup.a 6,S5    (75:25) (60:40)                                                                              (50:50)                                ______________________________________                                        0     100       100     100     100    100                                    0.125 99.8      85.4    100     100                                           0.25  99.5      84.3    100     98.9                                          0.5   99.9      77.3    87.8    97.0   100                                    1     99.3      40.7    60.8    80.4   84.2                                   2     99.0      13.4    37.5    81.6   76.9                                   3     100       0.0     35.1    63.1                                          4     99.9              19.4    50.9   56.9                                   5     99.7              12.2                                                  6     98.8              7.8     35.3   46.5                                   8     95.3              5.4     26.3   41.0                                   10    82.9              7.4                                                   12    61.3              6.2     22.2   38.7                                   15    44.6                                                                    16                              22 0                                          19    16.0              7.3            37.1                                   20                              20.3                                          23    12.0                                                                    24                              21.3   38.3                                   30                      4.2     22.2   37.7                                   ______________________________________                                         .sup.a Polycaprolactone                                                  

One-Year Study: 37° C. A second in vitro hydrolysis study was conductedat 37° C. in the manner described above. A somewhat larger particle size(to pass a #8 mesh sieve) was used in this study. The hydrolyses of fourexperimental polymers (two homopolymers and two 50:50 copolymers), aswell as a polycaprolactone control, were studied; the results appear inTable 9.

                  TABLE 9                                                         ______________________________________                                        IN VITRO HYDROLYSIS (37° C.)                                           % Mass Remaining                                                              Sample:                                                                       Time/                    C8,S5:C8,6                                                                            6,S5:6,6                                     weeks  PCL.sup.a                                                                              6,S5     (50:50) (50:50)                                                                              C8,S5                                 ______________________________________                                               100      100      100     100    100                                   0.43   101.7    82.6     99.8    98.3   89                                    l      100.2    80.5     99.6    96.2   83.1                                  2      100.1    78.3     100     95.7   79.6                                  3      99.7     75.5     98.6    94.9   78.6                                  4      99.8     76       98.3    96.8   78.7                                  6      99.8     80.7     98.5    97.8   85.3                                  9      100.1    72.7     96.5    94.4   76                                    13     99.3     67.1     95.2    94.5   74.4                                  18     99       62.2     94.7    94.7   76.1                                  24     99.6     58.3     95      92.7   72.2                                  30     99.2     51.8     94.9    --     71.2                                  36     99.3     44.6     96      91.1   70.6                                  44     99.1     34.3     93.2    90     67.9                                  52     98.7     26.4     94.7    87.4   65.8                                  ______________________________________                                         .sup.a Polycaprolactone                                                  

EXAMPLE VI In Vivo Implantation

One experimental 6,S5:6,6 (50:50) copolymer, one C8,S5:C8,6 (50:50)copolymer and a nylon 6,6 control were implanted subcutaneously in thebacks of male New Zealand white rabbits. One-inch-square film samples(abt. 0.0025 in. thick) of known mass were sterilized with ethyleneoxide before use. Three subcutaneous pockets were formed on the back ofeach anesthetized rabbit, and one sample of each polymer was implantedin each of 15 rabbits. The incisions were closed with stainless steelwound clips. Three animals were sacrificed at 2, 3, 8, 13, and 24 weeksafter implantation. At necropsy, the implants were recovered whenpossible, and the surrounding tissues were excised for histologicalexamination. The retrieved films were cleansed of adhering tissues anddried in vacuo at room temperature. The films were reweighed; theresults appear in Table 10.

                  TABLE 10                                                        ______________________________________                                        IN VIVO IMPLANTATION                                                          % Mass Recovered                                                              Time, Sample                                                                  wks   6,S5:6,6(50:50)                                                                             nylon 6,6                                                                              C8,S5:C8,6(50:50)                                ______________________________________                                        0     100           100      100                                              2     66.8          ND       64                                               3     88.2          ND       58                                               8     26.9          96.6     29.2                                             13    9.6           99.9     7.7                                              24    NR            96.9     NR                                               ______________________________________                                         NR = no polymer could be recovered                                            ND = result not determined                                               

The implanted copolymers were found to be highly fragmented after onlytwo weeks in vivo. After 24 weeks in vivo, most of the implants had beenabsorbed as judged by visual inspection, but the absorption was nottotal, because small fragments of polymer could be seen under themicroscope. The nylon 6,6 control implant did not lose mass or decreasein IV to any significant extent in 24 weeks.

In general, the tissue responses to the implanted copolymers wereconsidered relatively mild and were graded using criteria which includedfibrosis, inflammation, vascularity, edema, foreign-body reaction, andabscess formation. The polymers of this invention and nylon 6,6 gavesimilar mild responses with respect to fibrosis, inflammation, edema,foreign-body reaction, and vascularity.

EXAMPLE VII Drug/Polyamide Blends

Blends containing 25 wt % progesterone and similar blends containing 1to 5 wt % insulin were prepared by evaporation of trifluoroethanolsolutions containing a 6,S5 homopolymer, a 6,S5:6,6 (50:50) copolymerand a poly(DL-lactide-co-glycolide) copolymer ("DL-PLG"). Progesteroneand insulin were selected as the bio-active agents in these tests asrepresentative of therapeutic drugs in general, progesterone being asteroidal hormone of relatively low molecular weight and insulin being apolypeptide of relatively high molecular weight.

The blends were extruded into monolithic rods on a Tinius Olsenextrusion plastometer. The extrusion conditions appear in Table 11.

                  TABLE 11                                                        ______________________________________                                        EXTRUSION CONDITIONS                                                          Sample No.                                                                            Drug/polymer    Temp,   Extrusion                                                                            Diam                                   C389    Blend           °C.                                                                            wt, kg mm                                     ______________________________________                                        126-5   progesterone/homo-                                                                            70.3     7.19  2.11                                           polymer                                                               126-6   progesterone/50:50                                                                            130.9   27.49  1.23                                           copolymer                                                             126-7   progesterone/DL-PLG                                                                           72.4    20.40  1.63                                   136-1   insulin/DL-PLG  71.4    30.72  1.31                                   136-2   insulin/homopolymer                                                                           71.4    30.72  2.31                                   136-3   insulin/50:50 copolymer                                                                       166.0   30.72  1.23                                   ______________________________________                                    

EXAMPLE VIII Release of Drugs From Blends

The release of progesterone from drug/polymer blends was determined byimmersing triplicate samples of each blend in separate containers with25 mL of an aqueous solution containing 27.5 wt % ethanol. The receivingfluid was changed periodically for fresh ethanol solution, and solutionabsorbance was measured at 246.5 nm. A standard curve of absorbanceversus progesterone concentration was used to quantify the massreleased. The results appear in Table 12.

                  TABLE 12                                                        ______________________________________                                        IN VITRO RELEASE OF PROGESTERONE FROM                                         25% - LOADED MONOLITHIC RODS                                                                       Cumulative fraction of                                                        progesterone released                                    Polymer     Time, h  (Avg. of 3 samples)                                      ______________________________________                                        6,S5        0.5      0.33                                                                 1.0      0.53                                                                 2.0      0.85                                                     6,S5;6,6    0.5      0.20                                                     (50:50)     1.0      0.32                                                                 2.0      0.47                                                                 3.5      0.61                                                                 7.0      0.78                                                                 24.0     0.97                                                                 48.0     0.98                                                                 72.0     0.98                                                                 240.0    0.98                                                     DL-PLG      0.5      0.0084                                                   (75:25)     1.0      0.0086                                                               2.0      0.0088                                                               3.5      0.0092                                                               7.0      0.011                                                                24.0     0.017                                                                48.0     0.025                                                                240.0    0.068                                                    ______________________________________                                    

Experiments were also undertaken to prepare and test tablets containinginsulin and the aforesaid polymers. The tablets were prepared bycompression sintering at room temperature under about 100,000 psi.Controlled release was subsequently observed; about 40% of the insulinwas released from homopolymer-containing tablets in 48 hours. Therelease of insulin was examined by immersing triplicate samples of eachblend in separate containers with 1 mL of Sorenson's phosphate buffer,pH 7.3. The receiving fluid was exchanged for fresh buffer and analyzedfor insulin. The release profile obtained with implants prepared fromthe homopolymer appears in Table 13.

                  TABLE 13                                                        ______________________________________                                        IN VITRO RELEASE OF INSULIN FROM                                              25% - LOADED COMPRESSION SINTERED TABLETS                                     PREPARED WITH 6,S5 HOMOPOLYMER                                                Cumulation Fraction of Insulin Released                                                C389-147                                                             Time, h                                                                       2a                                                                            2b                                                                            2c                                                                            ______________________________________                                        1          0.13         0.12   0.13                                           2          0.17         0.15   0.15                                           3          0.21         0.19   0.18                                           19         0.29         0.31   0.27                                           45         0.43         0.44   0.37                                           ______________________________________                                    

Surprisingly, when either the homopolymers or the copolymers of thisinvention are degraded by hydrolysis, the loss of polymer mass occursapproximately linearly with time, especially during the early stages ofdegradation. While not being bound by this explanation, these zero-order(time independent) degradation kinetics suggest that the polymersdegrade either by a surface erosion mechanism or by an "unzippering"mechanism involving chain ends, rather than by random chain scissioningin the bulk of the polymer. Zero-order degradation kinetics clearlydistinguishes these polymers from the known poly(glycolides),poly(lactide-coglycolides), polycaprolactone, and similar aliphaticpolyesters, as well as the poly(ether-esters) and the poly(ester amides)of the prior art.

When polymers degrade in vitro and in vivo by mechanisms leadings tozero-order mass-loss kinetics, such polymers are especially useful informulating novel drug delivery systems (implants, microcapsules, etc.)for pharmaceuticals requiring constant, long term delivery rates.Moreover, they have exceptional utility in drug-releasing implantsdesigned to medicate food animals (pigs, sheep, cattle, chickens, etc.),because implants can be prepared from which no polymer residues remainin tissues after drug release is complete.

What is claimed is:
 1. An organic polymer, the structural formula ofwhich includesa backbone containing n biradical units of the formula##STR5## joined randomly with m biradical units of the formula ##STR6##wherein n is a positive integer; m is either zero or a positive integer;each R independently is a hydrocarbon radical; X₁ is --OH and Y₁ is --H,or X₁ and Y₁ together constitute a chemical bond in a lactam ring; X₂ is--OH and Y₂ is --H, or X₂ and Y₂ together constitute a chemical bond ina lactam ring; said backbone being capped with a radical selected from##STR7## --NH₂, and also ##STR8## when m is a positive integer; with theproviso that the polymer backbone contains lactam units when m is zero.2. A polymer according to claim 1 wherein m is zero and the polymer is ahomopolymer.
 3. A polymer of claim 2 wherein R is selected fromaliphatic and alicyclic groups containing 4-14 carbon atoms.
 4. Apolymer of claim 3 wherein R is an aliphatic group selected frompentamethylene and hexamethylene.
 5. A polymer of claim 3 wherein R isan alicyclic group selected from 1,4-cyclohexanebis(methyl) and4,4'-methylenebis(cyclohexyl).
 6. A polymer of claim 4 wherein R ishexamethylene.
 7. A polymer according to claim 1 wherein m is a positiveinteger and the polymer is a copolymer.
 8. A polymer of claim 7 whereineach R is selected from aliphatic and alicyclic groups containing 4-14carbon atoms.
 9. A polymer of claim 8 wherein said aliphatic groups areselected from pentamethylene and hexamethylene and said alicyclic groupsare selected from 1,4-cyclohexanebis(methyl) and4,4'-methylenebis(cyclohexyl).
 10. A polymer according to claim 1 whichis cross-linked via a difunctional reagent which reacts with hydroxylgroups.
 11. A polymer according to claim 10 wherein said reagent is adiisocyanate.